Method for low-voltage termination of cardiac arrhythmias by effectively unpinning anatomical reentries

ABSTRACT

A method for extinguishing a cardiac arrhythmia utilizes destructive interference of the passing of the reentry wave tip of an anatomical reentry through a depolarized region created by a relatively low voltage electric field in such a way as to effectively unpin the anatomical reentry. Preferably, the relatively low voltage electric field is defined by at least one unpinning shock(s) that are lower than an expected lower limit of vulnerability as established, for example, by a defibrillation threshold test. By understanding the physics of the electric field distribution between cardiac cells, the method permits the delivery of an electric field sufficient to unpin the core of the anatomical reentry, whether the precise or estimated location of the reentry is known or unknown and without the risk of inducting ventricular fibrillation. A number of embodiments for performing the method are disclosed.

RELATED APPLICATION

This application is a continuation of application Ser. No. 13/464,537,filed May 4, 2012 and now issued as U.S. Pat. No. 8,639,325, which is adivision of application Ser. No. 11/266,755 filed Nov. 3, 2005, nowissued as U.S. Pat. No. 8,175,702, which claims the benefit of U.S.Provisional Application No. 60/624,978, filed Nov. 4, 2005, and of U.S.Provisional Application No. 60/697,858, filed Jul. 7, 2005, each ofwhich is hereby fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to a method for termination ofcardiac arrhythmias and, more specifically, to a method forextinguishing an arrhythmia by destructive interference of the passingof the reentry wave tip of an anatomical reentry through a depolarizedregion created by a relatively low voltage electric field in such a wayas to effectively unpin the anatomical reentry.

BACKGROUND OF THE INVENTION

It is well-known that rotating waves of electrical activity are a factorin potentially dangerous cardiac arrhythmias such as ventriculartachycardias and ventricular fibrillations (“ventricular tachycardiaevents”). The rotating waves, or reentries, that are responsible forventricular tachycardia events are classified into two categories: 1)functional reentries, which involve freely rotating waves; and 2)anatomical reentries, where a wave rotates around an obstacle such as ablood vessel or piece of ischemic tissue. The latter are referred to asbeing ‘pinned’ by the obstacle. Traditional defibrillation is not apreferred way of dealing with such rotating waves because defibrillationresets electrical activity everywhere in the heart and uses high voltageshocks, which have undesirable side effects.

One common method of attempting to terminate these rotating waves orreentries is antitachycardia pacing (ATP). ATP has a high rate ofsuccess in dealing with functional reentries, but is not as effectiveagainst anatomical reentries. Generally, if ATP is not effective, adefibrillating shock of large amplitude is applied directly to cardiacmuscle.

The reasons ATP is not always successful can be found in the complexityof the system. In one-dimension, the situation involving reentries iswell-understood and relatively simple. A reentry essentially consists ofa pulse rotating along a closed ring. To terminate a reentry, it isenough to deliver a stimulus close to the tail of the rotating pulse.The stimulus should be delivered inside the critical time interval (theso-called vulnerable window, VW). Under these circumstances, only onepulse is created and it propagates in the direction opposite to thereentry pulse. Ultimately, it collides with the reentry pulse, leadingto complete annihilation. If an ATP stimulus is delivered to quiescenttissue, it creates two counter propagating pulses and the reentry is notterminated. The description above assumes, however, that the medium ishomogeneous.

The situation is more complex in two dimensions. In this case, ananatomical reentry is a spiral wave rotating around an obstacle. Toterminate the reentry, it is necessary to create a wave that canannihilate the rotating wave. This is more difficult than in theone-dimensional scenario because, in the two-dimensional scenario, thewave is characterized not only by its sense of rotation, but also by acomplete wave form. As in the one-dimensional situation, an ATP stimulusmust be delivered inside the vulnerable window, but this condition aloneis not sufficient. When the ATP electrode is situated far from theobstacle, the nucleated wave has a free end that is separated from theobstacle. Thus, ATP is only successful when the free end merges with theobstacle. Only then, two counter propagating waves annihilate and theanatomical reentry is terminated. This is possible only if the distancefrom the free end of the nucleated wave to the obstacle is smaller thana critical distance (of the order of the core size of a free vortex,from several cm to several mm in cardiac muscle).

On the other hand, when a stimulating electrode is placed far from theobstacle, then ATP does not terminate the reentry, but instead creates afree reentry in addition to the anatomical one. When ATP is notsuccessful, it is usually followed by conventional defibrillationtechniques, which have unwanted side effects. These effects may include:(1) transient ectopy, tachycardia or induction of ventricularfibrillation; (2) depression of electrical and mechanical functions; (3)bradycardia, complete heart block and increased pacing thresholds; (4)atrial and ventricular mechanical dysfunction (stunning), which isdirectly related to the strength of shocks; (5) significant elevation ofTroponin I serum level in patients after spontaneous cardioverterdefibrillator shocks; (6) decrease of the myocardial lactate extractionrate by mitochondria. In addition to physical damage to the heartmuscle, defibrillation therapy is also associated with psychologicalside effects. High energy discharge of a defibrillator in a consciouspatient is painful and extremely unpleasant. Recent clinical studieshave demonstrated that ICD patients have a significantly higherincidence of anxiety, depression, and panic disorders than do thegeneral population.

What is needed, therefore, is a method for terminating an anatomicalreentry using an energy level lower than that of conventionaldefibrillation techniques. Further, it is desirable that such a methodbe effective even when the precise location of the reentry is unknown.

SUMMARY OF THE INVENTION

The present invention provides a method for extinguishing a cardiacarrhythmia by destructive interference of the passing of the reentrywave tip of an anatomical reentry through a depolarized region createdby a relatively low voltage electric field in such a way as toeffectively unpin the anatomical reentry. Preferably, the relatively lowvoltage electric field is generated by electrical unpinning shocks thatare intended to be lower than a lower limit of vulnerability asestablished, for example, by a defibrillation threshold test. Byunderstanding the physics of the electric field distribution betweencardiac cells, the method permits the delivery of an electric fieldsufficient to unpin the core of the anatomical reentry, whether theprecise or estimated location of the reentry is known or unknown andwithout the risk of inducting ventricular fibrillation. A number ofembodiments for performing the method are disclosed.

The method of terminating anatomical reentrant tachyarrhythmias utilizesone or more low voltage unpinning shocks that are applied in such a wayas to effectively unpin the reentry from its core that is stabilized ata myocardial heterogeneity such as a scar. Preferably, the unpinningshocks are sub-threshold low voltage shock(s) that generate an electricfield that is approximately 5-10 times weaker than the electric fieldgenerated by a conventional defibrillation shock and preferably below anexpected lower limit of vulnerability for a defibrillation threshold,while greater than conventional pacing or ATP pulses.

In one embodiment, this method utilizes a theory of virtual electrodepolarization (VEP) that predicts the creation of hyperpolarized anddepolarized regions on opposite sides of a functional or anatomicalheterogeneity in response to an applied external electric field. Theareas of depolarization can give rise to secondary sources ofexcitation. When shock application is properly timed relative to thereentry wave tip, these secondary sources are induced at the anatomicalheterogeneity that serves as the core of reentry. Therefore, VEP can beused to destabilize and unpin a reentrant arrhythmia.

In a preferred embodiment of the present invention, anti-repinning (ARP)pulses are applied after the low voltage unpinning shocks to avoidimmediate repinning of the anatomical reentry at its core and facilitatecomplete termination of the now unpinned reentry that has beentransformed into a functional reentry. Conventional ATP pulses havedifficulties terminating anatomical reentry when the pacing site islocated at a distance from the reentry core. However, there are no suchdifficulties associated with ATP termination of a functional reentry.Therefore, once the reentry is unpinned from its anatomical core, ARPpulses in accordance with the present invention can be effectivelyadministered for terminating these now functional reentries andpreventing their reattachment to a new core.

In this preferred embodiment, the ARP pulses are applied for purposes ofcompleting the termination of the reentries, not for purposes ofregulating a cardiac heart rate. In this way, the ARP pulses ascontemplated by the preferred embodiment of the present invention aresignificantly different that the few prior art approaches such as U.S.Pat. Nos. 4,384,585, 5,265,600, 5,676,687 and 6,157,859, that haveattempted to use conventional pacing pulses for the purpose ofregulating heart rate, especially after atrial cardioversion.

In one embodiment of the present invention, the method is accomplishedby establishing a termination window (TW), applying one or more lowenergy unpinning pulses in the target TW to unpin a rotating waveassociated with one or more anatomical reentries causing the ventriculartachyarrhythmia, and immediately following the low energy unpinningshocks with anti-repinning (ARP) pulses to exterminate any unpinned,functional reentries. In this embodiment, there is no need to attempt toverify successful conversion of the arrhythmia prior to deliver of theARP pulses because the process of terminating the arrhythmia inaccordance with this embodiment of the present invention is essentiallya multiple stage process of first unpinning anatomical reentries andthen extinguishing all functional reentries, including any unpinned andnow functional reentries that were originally anatomical reentries. Inone variation of this embodiment, a dominant frequency (DF) for aventricular tachyarrhythmia is determined based on ECG data. The DF isthen used to establish the target TW. In an exemplary embodiment, theperiod defined by 1/DF would be divided by a small number, such asthree, to establish the termination window.

In some embodiments of the present invention, the method is accomplishedby identifying an estimated location of the anatomical reentry and usingthe information on the location of the anatomical reentry and thelocation and configuration of an electrode arrangement to estimatepropagation delays for purposes of timing delivery of the unpinningshock(s). Unlike earlier attempts at cardioversion, the presentinvention does not time delivery of the unpinning shocks in relation tosome aspect of the QRS complex of the cardiac signal of a patient.Instead, these embodiments of the present invention time delivery of theunpinning shocks based on measured, estimated or empirical data of thedelay for a given relationship between the locations of the particularelectrode configuration and the location of the heterogeneity associatedwith the anatomical reentry. Alternatively, other embodiments of thepresent invention utilize initially random timing of delivery of theunpinning shocks that is preferably coupled with empirical heuristicrefinement of the timing and patterns of delivery of unpinning shocks.

One embodiment of the estimated timing approach utilizes roughapproximation of the estimated location of the anatomical reentry byevaluating ECG signals received from at least three pairs of sensingelectrodes in order to triangulate the estimated location in 3D space.This embodiment can be implemented in either a real time configurationor in an embodiment in which the estimated location of likely anatomicalreentries is determined, for example, during defibrillation thresholdtesting during an implantation procedure for the electrode arrangementand/or an implantable cardiac stimulation device, such as an implantablecardioverter defibrillator (ICD). In this later embodiment, thetriangulation of the estimated location of one or more existingheterogeneities in the heart of a patient that may be likely to be thesource of future anatomical reentries is based on the identification ofthose existing heterogeneities during defibrillation threshold (DFT)testing.

Unlike existing approaches to DFT testing, one embodiment of the presentinvention utilizes the DFT testing process that is part of aconventional implantation procedure for a cardiac stimulation device todetermine an upper limit of vulnerability (ULV) that will be used toestablish a safety margin for the defibrillation therapy to be deliveredby the implantable device. Instead of determining just a ULV for a givenpatient, this embodiment of the present invention also determines alower limit of vulnerability (LLV) below which electrical shocks fromthe electrode arrangement for the given implantable device will notinduce fibrillation. This LLV is the utilized in a preferred embodimentas an upper bound for the sub-threshold, low voltage shocks that areutilized in accordance with the method of the present invention toeffectively unpin anatomical reentries. Alternatively, the LLV may beestablished based on empirical or statistical data for similarlysituated patients.

Another embodiment uses electrocardiographic imaging (ECGI) tonon-invasively construct a more detailed representation of electricalactivity of the heart for purposes of identifying heterogeneities thatare likely to be responsible for anatomical reentries. ECGI systems canbe used to solve the so-called “Inverse” problem of figuring out how topredict a source of an electric field based on measurements of thatfield made at a distance. One such ECGI system is described inRamanathan, C. et al. “Noninvasive electrocardiographic imaging forcardiac electrophysiology and arrhythmia,” Nature Medicine,10.1038/nm1011, March 2004, a copy of which is attached and thedisclosure of which is hereby incorporated herein by reference. Such anECGI system could be implemented either during DFT or, in the case ofexternal defibrillation, for example, in real time by an appropriateelectrode configuration.

In this embodiment, during the arrhythmia, with no shock delivered, twomeasurements are performed from the constructed map (i) rotation phasephi of the reentry tip, and (ii) position of the reentry core. Fromthese measurements, the following values are calculated: (i) thedirection E^ of the electric field near the core, and (ii) the rotationphase phi^ of the reentry tip with respect to the direction E^. Anunpinning shock in accordance with the present invention is thensynchronized with event phy^=0. The shock is delivered at timet=t(phy^=0)+APD, where APD is the action potential duration determinedfrom an ECG record. This same technique can be utilized for findingestimated locations of the secondary or “virtual” electrodes associatedwith the heterogeneities.

In another embodiment, the estimated location of the anatomical reentrycausing a cardiac arrhythmia could be determined in real time based onsignal and morphology analysis of ECG signals from multiple sensingelectrode configurations, such as RV-RA electrode vs. RV-can vs. RA-canfor purposes of triangulating the estimated location in 3D space.

In other embodiments of the present invention, no attempt is made toidentify an estimated location of the anatomical reentry. In theseembodiments, the method is implemented by delivering sub-thresholdshocks that have a high probability of accomplishing the objective ofunpinning the anatomical reentry without knowing the location of theanatomical reentry.

In one embodiment, the method is accomplished by detecting and storingthe waveform of the electrograms (EG) recorded from the patient's heart,then determining the maximum negative derivative of the recordedwaveform. A set of threshold values is then calculated for the waveform,while the negative derivative of the waveform is continuouslycalculated. When the negative derivative exceeds a third thresholdvalue, a timer is started. When the time on the timer exceeds thepatient-specific individually adjusted delay, a reentry terminationshock is delivered to the patient's heart. Time of delivery of asub-threshold shock is chosen so that the virtual electrode polarization(VEP) would be created at the anatomical obstacle around which theanatomical reentry rotates, at the descending phase of AP of thereentrant wave.

In another embodiment, multiple unpinning shocks are utilized to presentalternative wave fronts to the anatomical reentry in order to increasethe likelihood of destructively interfering with the wave tip. One suchembodiment utilizes multiple (e.g., 3-4) unpinning pulses delivered overa TW period of 100-150 ms, where all of the pulses are delivered throughthe same electrode path. Another such embodiment utilizes multipleunpinning pulses that are delivered over a short period, but aredelivered over different electrode paths so as to produce the equivalentof a vector rotating field to the anatomical reentry.

In another embodiment, the process of empirically determining a best-fittiming for delivery of the unpinning shocks is accomplished by anadaptive routine implemented in an implantable device, for example. Inthis embodiment a low energy termination window (TW) is defined to beapproximately equal to about ⅕^(th) of the rotation period of theanatomical reentry. During a period of several second necessary tocharge the high voltage capacitor to deliver a defibrillation shock, themethod of the present invention is accomplished by iteratively havingthe device deliver an unpinning shock followed by ARP timed to a TW thatis set to a delay of T/5 from the indication of the anatomical reentryin the ECG data. After a period of about a second, the ECG data isanalyzed to determine if the arrhythmia has been converted. If so, thenthe device stores the time delay and utilizes this time delay as theinitial time delay to attempt for any subsequent arrhythmia episodes. Ifthe arrhythmia has not been converted, then the delay is set to a periodof 2 T/5 from the indication of the anatomical reentry in the ECG dataand the process of delivering the unpinning shock followed by ARP isrepeated. The entire process is repeated if the previous delay period isunsuccessful until either all possible TW's have been attempted, oruntil the capacitor has been fully charged for delivery of a highvoltage defibrillation shock. In subsequent episodes, the device woulduse the delay for TW that empirically resulted in the best fit for thelast successfully converted cardiac arrhythmia. In one variation of thisembodiment, multiple successful delays would be stored by the device anda heuristic learning algorithm and/or predictive algorithm would be usedto determine an order of attempting the multiple successful delays forattempting to convert a new cardiac arrhythmia using an unpinning shockthat is, preferably, followed by ARP.

In one alternative embodiment of the present method, the method alsoincludes the step of determining whether the unpinning shock wasdelivered within a pre-set safety time period. If the unpinning shockwas not delivered within a pre-set safety time period, a defibrillationshock is delivered at the time of expiration of the safety time period.

In another alternative embodiment of the present method, the method alsoincludes the step of determining whether the anatomical reentry wasterminated. If the reentry was not terminated, a defibrillation shock isdelivered at the time of expiration of the safety time period.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the dipole, quadrupole, and hexapole patterns induced byan electric field in the bidomain model of cardiac tissue.

FIG. 2 depicts the basic mechanism of unpinning an anatomical reentry.The depiction utilizes the FitzHugh and BR models.

FIG. 3 is a graph illustrating the unpinning window for the BR model andtwo variations thereof.

FIG. 4 illustrates the wave detachment observed with the standard BRmodel. The detachment is diminished with the modified BR modelsdescribed herein.

FIG. 5 is a graph illustrating different unpinning mechanisms observedfor higher values of pulse intensity.

FIG. 6 illustrates an unpinning mechanism at larger voltage levels.

FIG. 7 is a graph illustrating the dependence of the unpinning thresholdelectric field on the angle of application of the current with respectto cardiac fibers.

FIG. 8 depicts an unpinning scenario observed with small obstacles.

FIG. 9 is a graph showing the threshold of unpinning and termination oftachycardia in an isolated superfused right ventricular preparation fromrabbit heart.

FIG. 10 is a flow diagram illustrating the one embodiment of the methodof the present invention.

FIG. 11 is a block diagram of circuitry used to modulate time of shockapplication in accordance with one embodiment of the present invention.

FIG. 12 a shows typical confocal microscopy image showing predominatelyphosphorylated Cx43 (red) on the superfused surface of the tissue andpredominately unphosphorylated Cx43 (green) in the mid-myocardium.

FIG. 12 b shows signal intensities for phosphorylated andunphosphorylated Cx43 signals from the preparation pictured in FIG. 12a. These signals were averaged across a 1.26 mm section of tissue atincreasing distances from the superfused surface of the tissue.

FIG. 12 c shows a surface plot of signal intensities from thepreparation pictured in FIG. 12 a.

FIG. 12 d shows mean signal intensities from 3 experimental animals.

FIG. 13 a shows an activation map for pacing at a constant interval of300 ms from location indicated with a star. Black arrow pointing tocrowded isochrones indicates an area of slow conduction.

FIG. 13 b shows a preparation photograph overlapped with the trajectoryof points of phase singularity indicating the cores of two differentstable reentries whose isochronal maps are shown in FIGS. 13 c-13 d.

FIG. 13 c shows an isochronal map for a stable reentry rotatingcounterclockwise with 10 ms isochrones. Trajectory of points of phasesingularity is shown with a yellow line. The core of this reentrycorresponds to the area of slow conduction in FIG. 13 a.

FIG. 13 d shows an isochronal map for a stable reentry rotatingclockwise with 10 ms isochrones. Trajectory of points of phasesingularity is shown with a cyan line.

FIG. 13 e shows optical traces recorded from reentry in FIG. 13 d.

FIG. 14 a shows a steady-state isochronal map with 10 ms isochrones.

FIG. 14 b shows a phase-plane map 1 ms before shock application. Whitecircle indicates location of the phase singularity.

FIG. 14 c shows a phase-plane map 10 ms after shock application showinga new region of depolarization near the reentry core.

FIG. 14 d shows optical traces from the locations indicated withcorresponding colored boxes in FIG. 14 b. Shock-induced depolarizationcan be observed in the cyan trace.

FIG. 14 e shows local ECG recording from surface of the preparation.

FIG. 14 f shows a polar plot of successful and unsuccessful shocksapplied throughout all phases of reentry.

FIG. 15 a is a steady-state isochronal map with 10 ms isochrones forunpinning of reentry by virtual-electrode induced excitation of thereentry core without termination.

FIG. 15 b is a phase-plane map 1 ms before shock application. The phasesingularity of the mother rotor is located in the center of thepreparation.

FIG. 15 c is a phase-plane map 10 ms after shock application showing anew region of depolarization near the reentry core.

FIG. 15 d is an optical trace from a location near the reentry coreindicated with a cyan box in FIG. 15 b.

FIG. 15 e is a local ECG recording from surface of the preparation.

FIG. 15 f is a polar plot of successful and unsuccessful shocks appliedthroughout all phases of reentry.

FIG. 16 a is a steady-state activation map of reentry which uses a 3Dtrabecula in the reentry path of an isthmus mechanism of termination.Isochrones are 10 ms apart.

FIG. 16 b is a polar plot of successful and unsuccessful shocks appliedthroughout all phases of reentry.

FIG. 16 c is an optical recording from location indicated with a cyanbox in FIG. 16 a.

FIG. 16 d is a local ECG recording from surface of the preparation.

FIG. 17 is a graph of a survival analysis of terminated reentries versusshock strength.

FIGS. 18 a-18 c are images of endocardial infarction border zone inacute and chronic models of infarction thin.

FIG. 19 a is a series of graphs showing incidence and location ofarrhythmias in a chronic infarction model.

FIG. 19 b is a series of images showing corresponding incidence andlocation of arrhythmias in a chronic infarction model in FIG. 19 a.

FIG. 20 illustrates preliminary results from a version of a model of therabbit heart with acute and chronic states of infarction.

FIG. 21 shows a schematic diagram and photograph of a panoramic opticalsystem.

DETAILED DESCRIPTION OF THE DRAWINGS

The present invention provides a method of unpinning and terminating ananatomical reentry, whether the precise or estimated location of thereentry is known or unknown. A background discussion of the mathematicaland scientific basis underlying the monodomain and bidomain cell modelswhich the present invention builds upon is presented, followed by adiscussion of the present invention and some of the experimental dataand results supporting the present invention.

Intracellular clefts in cardiac tissue are small areas—smaller than thecardiac cells themselves—resulting in complex electrical patterns. For apoint injection of current, these clefts create a quadrupoledistribution of membrane potential near an electrode. Near an obstacle,an electrical field creates a hexapole distribution superimposed over adipole. This is valid also for an obstacle around which an anatomicalreentry rotates.

Dipole, quadrupole, and hexapole patterns induced by an electric fieldin a bidomain model of cardiac tissue are shown in FIG. 1. FIG. 1( a)shows a dipole, FIG. 1( b) a quadrupole, and FIG. 1( c) a hexapole. FIG.1( a) illustrates the result of an object 6 mm in diameter, with ananisotropy ratio a=1, E=0.2 V/cm. FIG. 1( b) illustrates the result of apoint-based injection of current I=1.8 μA, a=10. FIG. 1( c) is the sameobject as in FIG. 1( a), where a=10. Contours are drawn at intervals of0.4 mV. The bidomain model is used with the following values:G_(m)=0.165 mS/cm², σ_(ex)=σ_(ey)=σ_(ix)=14.4 mS/mm, σ_(iy)=1.44 mS/mm,β=2000 cm⁻¹.

The present invention focuses on how an electric field may be used tounpin an anatomical reentry in terms of how to unpin a rotating vortex.The minimal energy required for an electrical field that can accomplishthe unpinning, as estimated theoretically, is ˜100 times less than theenergy traditionally used in defibrillation (FIG. 3; the energy isproportional to the electric field squared). In rabbit heartsexperiments, the observed decrease of energy was on the scale 10-20times as compared to conventional defibrillation. The following exampledemonstrates this.

Example

The model describes the extracellular potential, φΦ_(e), and theintracellular potential, φΦ_(i):

$\begin{matrix}{{{{\nabla{\cdot \sigma_{i}}}{\nabla\phi_{i}}} = {{\beta\left\lbrack {{C_{m}\frac{\partial}{\partial t}\left( {\phi_{i} - \phi_{e}} \right)} + I_{ion}} \right\rbrack} - I_{i}}},} & (A) \\{{{\nabla{\cdot \sigma_{e}}}{\nabla\phi_{e}}} = {{- {\beta\left\lbrack {{C_{m}\frac{\partial}{\partial t}\left( {\phi_{i} - \phi_{e}} \right)} + I_{ion}} \right\rbrack}} - {I_{e}.}}} & (B)\end{matrix}$where σ_(i) and σ_(e) are the conductivity tensors, and I_(i) and I_(e)are the externally injected currents in the intracellular andextracellular spaces, respectively. β β is the ratio of membrane surfacearea to tissue volume, C_(m) is the membrane capacitance per unit areaof the cell membrane, and I_(ion) is the ionic current.

Equations (A) and (B) were used, along with ionic current (I_(ion)) asdescribed by either the FitzHugh or BR model, or by the modifications ofthe BR model, above. A rotating waves pinned to a circular obstacle wasnumerically simulated, and the effects of an electric field fordifferent timings and intensities were observed. For the relativelysimple FitzHugh model, the entire set of possibilities leading tounpinning was explored. For the BR model, only situations relevant tocardiology (i.e. those with a weak electrical field) were explored.

Rotating waves were numerically simulated in the full bidomain modelwith nonlinear ionic currents (using equations (A) and (B), above). Thebasic mechanism of unpinning can is described in FIG. 2. FIG. 2( a)illustrates the basic mechanism of unpinning. This portion of FIG. 2relies on the FitzHugh model of a pinned spiral rotating wave at varioustime intervals as indicated in the figure. At time t=0 ms, a pinnedspiral rotating wave S is shown. The wave is pinned to an obstacle,represented by the circle at the center of the wave. An electric pulse,20 ms long, is applied from t=20 to 40 ms. At time t=40 ms, a dipole(D−, D+) is induced around the obstacle by an electric field having astrength of 0.52 V/cm. At t=80 ms, the positive part of the dipole D+nucleates a new wave W. Near the obstacle, this waves propagates onlyclockwise (see t=200 ms, for example) due to the time of application ofthe pulse. At t=280 ms, the waves W and S collide. At t=360 ms, afterannihilation of the colliding parts, the rotating wave is unpinned. Ifthe medium is small enough (i.e. the boundary is located at the dashedline shown in FIG. 2( a)), then the reentry is terminated as shown att=360 ms.

It is important to note that the wave W with the desired properties canbe created only with proper timing of the electric pulse. Similar toATP, if the pulse is delivered earlier it fits inside the restorationpart of the propagating wave (i.e. inside the refractory tail), and nonew wave will be nucleated. If the pulse is delivered much later, itwill nucleate two counter propagating waves. The correct interval ofstimulation (referred to as the termination window, VW, as noted above)is determined by the condition that the image of the nucleated wave W inthe phase space should contain the Maxwell point inside. A more evidentinterpretation is: the nucleated wave W can propagate only in onedirection if a part of its boundary has positive velocity (becoming afront of the wave) and another part has a negative velocity (becomingthe tail of a wave). This condition sets both the time and voltagelimits of the unpinning window.

FIG. 2( b) relies on the modified BR model (BR_(d)). Again, a model of apinned spiral rotating wave at various time intervals is shown. At timet=95 ms, the D+ component of the dipole D−, D+ is induced around theobstacle (indicated by the circle at the center of the rotating wave)using an electric field of strength 0.5 V/cm. At t=130 ms, a new wave Wis created by D+. Near the obstacle, this wave, denoted W−, propagatesonly clockwise. In this model, the wave W− does not contact theobstacle. At t=160 ms, the waves W− and S collide. A small piece of thepinned spiral wave S is not unpinned, but it decays. At t=200 ms, afterannihilation of W− and S, the rotating wave rotates freely. Theasymmetry of the nucleated wave W (which propagates only in clockwisedirection) requires proper timing of the electric pulse, just at thetail of wave S. Without proper timing, the nucleated wave W eitherpropagates in both directions, as in FIG. 2( c), below, or completelyvanishes.

FIG. 2( c) also relies on the modified BR model, (BR_(d)), andillustrates a failed unpinning. A pinned spiral wave is shown at t=180ms. At t=185 ms, the depolarized region D+ is created by an electricpulse of 0.5 V/cm. At t=200 ms, D+ gives rise to a wave W, whichcollides with S. At t=240 ms, the wave S continues to rotate around theobstacle.

From a practical standpoint, it is necessary to determine precisely howan electric field should be applied for an unpinning. That is, it isnecessary to determine at what time the electric field should beapplied, and at what strength. FIG. 3 shows the threshold electric fieldused to achieve unpinning, versus the time at which the electric fieldwas applied. The results shown in FIG. 3 come from the three BR modelsdescribed above (the original model and the two modified versionsthereof). Importantly, unpinning is achieved in all three models using alow electric field (<0.5 V/cm). The date lines on the graph in FIG. 3indicate the threshold amplitude of the electric pulse to achieveunpinning. A pulse of amplitude less than 0.5 V/cm can unpin for all ofthe versions of the ionic model. The BR_(d) model is the most favorablefor unpinning. The original BR model exhibits the smallest unpinningwindow, due to wave detachment.

By referring to FIG. 3, it can be seen why the modified models BR_(d)and BR_(df) were introduced above. As noted, the BR model has a smallerunpinning window than the modified models. This is due to an unexpectedphenomenon, illustrated in FIG. 4. The figure shows that the wavenucleated by the electric field appears unpinned from the obstacle,although the rotating wave is pinned to it. This is due to the smallersize of the nucleated wave. The BR_(d) and BR_(df) models eliminate thisphenomenon.

The basic unpinning mechanism is the same for both the FitzHugh and BRmodels given a low electric field (˜0.5 V/cm). An analysis for unpinningwith a larger voltage (>2 V/cm) appears below. This analysis utilizesthe simpler FitzHugh model.

Extensive numerical investigation provides unpinning thresholds as afunction of the time of the pulse. The results are given in graph formin FIG. 5. As the graph indicates, new scenarios appear relative to thelow electric field results provided in FIG. 3, above. These newscenarios involve components of the potential, H_(1,2) ⁺, and/or thehyperpolarized regions of the dipole (D−). In the curves shown in FIG.5, these scenarios are characterized by the lobe of the membranepotential distribution that interacts with the spiral wave.

The unpinning scenario is shown in FIG. 6. The pinned wave S is shown att=−80 ms. An electric shock of 4.5 V/cm is applied at t=−60 ms. At t=−40ms, the depolarizing part of the dipole coincides with the rotatingwave. Both the dipole and the hexapole are seen. At t=0 ms, a new wave Wis created by the hexapole component H₂+. The waves created by H₁+ andby D+ merge with S. The wave W, propagating clockwise at t=40 ms,collides with the original rotating wave at t=80 ms. Annihilation of thecolliding parts occurs from t=120 ms to 160 ms, and the wave is unpinnedat t=240 ms.

In the heart, fibers are oriented at various angles. These variousangles θ₁ (equations (J) and (K), above) will contribute to theunpinning. This can be understood by the analysis below. The electronicconstant perpendicular to the fibers is smaller than parallel to them.For large obstacles (radius R>>λ), the maximum potential at the obstacledepends approximately linearly on the electronic constant λ. Linearapproximation of the exact solution gives:

$\begin{matrix}{{V_{m}^{0}\left( {{r = R},{\theta = 0}} \right)} \approx {{\lambda\left( {1 - \frac{\lambda}{2R}} \right)}{E_{0}\left( {R\operatorname{>>}\lambda} \right)}}} & (N)\end{matrix}$

When the electric field is rotated by 90°, λ_(y) instead of λ_(x) isused in the equation. As a result, the electric field will have asmaller effect when applied along y than along x, since the electronicconstant is smaller:

$\lambda_{y} = {\sqrt{\frac{2}{{1 + a}\mspace{11mu}}}\lambda_{x}}$where a=σ_(ix)/σ_(iy)>1 is the anisotropy ratio. The threshold ofexcitation, and of unpinning, is thus larger when the field is appliedparallel to y.

More quantitatively, the perturbation analysis allows justification ofthe increased unpinning threshold. The transversal case θ_(i)=90° can bededuced from the parallel case by interchanging ε by −ε in the equationdescribing the intracellular tensor, above. Thus, dipolar and hexapolarcorrections of the depolarized region have the opposite sign. Thiscauses the unpinning threshold to become larger. The dependence of theunpinning threshold on the fiber direction is shown in FIG. 7. As can beseen, the threshold value remains low for almost all angles.

The termination threshold is also dependent on the size of the obstacleto which the rotating wave is pinned. For large obstacles (radiusR>>λλ), the maximum potential at the obstacle depends approximatelylinearly on the electronic constant λλ:

${V_{m}^{0}\left( {{r = R},{\theta = 0}} \right)} \approx {{\lambda\left( {1 - \frac{\lambda}{2R}} \right)}{E_{0}\left( {R\operatorname{>>}\lambda} \right)}}$

Very small obstacles (˜1 mm) are not capable of pinning rotating waves.In this situation, equation (N) is approximately valid because fortypical cardiac tissue, λλ˜1 mm. Hence, the dependence of thedepolarization on the obstacle size is weak for obstacle sizes thatsupport rotating waves. The unpinning window, however, is modified.

For obstacles not much larger than the limiting size to sustain arotating wave, a new unpinning mechanism arises. This mechanism is shownin FIG. 8. At t=65 ms, D+ is induced by an electric field of strength0.85 V/cm. When the electric field nucleates a wave W (t=78 ms) in thepartially refractory region, it propagates away from the obstacle, asseen at t=104 ms, and decays (t=130 ms). The pinned wave meets therefractory tail of W and unpins at t=156 ms to 182 ms. Thus, for a smallobstacle, the unpinning window becomes smaller in time but larger inphase units. For intermediate obstacles, the wave detachment maydecrease the unpinning window as occurs for the original BR model.Finally, for large enough obstacles, all models have a low unpinningthreshold and the same unpinning mechanism operating at this lowelectric field.

FIG. 9 is a graph showing the threshold of unpinning and termination oftachycardia in an isolated superfused right ventricular preparation fromrabbit heart. Shock strength is shown in V/cm. Timing of the shockapplication is shown in radians, assuming that the period of tachycardiais 6.28 radians (two pi).

FIG. 10 provides a flow diagram illustrating one embodiment of themethod of the present invention. Each of the steps in the method hasbeen assigned a number in the drawing for the sake of clarity.Beginning, then, at the numeral 10, the VF/VT of the patient isconfirmed and a high-voltage capacitor is charged. The initial programparameters and safety time counter are also initialized. Next, thenegative signal derivative is calculated and the threshold values 1, 2and 3 are determined. In addition, a flag is set to zero (12). Thenegative signal derivative is calculated once again (14). Then, adetermination is made as to whether the negative signal derivative issmaller than threshold 1 and whether the flag is still set to zero (16).If the answer to both of these determinations is ‘yes,’ then the flag isset to 1 (18) and the method proceeds to the step indicated by thenumeral 30. If the answer to either determination is ‘no,’ the methodproceeds to the step indicated by the numeral 20. If the method hasproceeded to the step indicated by the numeral 20, a determination ismade as to whether the negative signal derivative is larger thanthreshold 2 and whether the flag is set to 1. If the answer to bothdeterminations is ‘yes,’ then the flag is set to 2 (22) and the methodproceeds to the step indicated by the numeral 30. If the answer toeither determination is ‘no,’ then the method proceeds to the stepindicated by the numeral 24. If the method has proceeded to the stepindicated by the numeral 24, a determination is made as to whether thenegative signal derivative is smaller than threshold 3 and whether theflag is set to 2. If the answer to both of these determinations is‘yes,’ then the method proceeds to the step indicated by the numeral 26.After waiting for the patient's individually adjusted delay (26), ashock is delivered to the patient's heart (28). If the answer to eitherdetermination in the step indicated by the numeral 24, above, is ‘no,’then the method proceeds to the step indicated by the numeral 30. Adetermination is made as to whether the safety time counter has reachedzero (30). If the safety time counter has reached zero, a standarddefibrillation shock is delivered (32). If the safety time counter hasnot reached zero, the method proceeds to the step indicated by thenumeral 34. A VF/VT confirmation is performed (34). If VF/VT is notconfirmed, the method is aborted. If VF/VT is confirmed, the methodreturns to the step indicated by the numeral 14 and proceeds as above.

The above analysis demonstrates the present mechanism of unpinningspiral waves by using a small electric field. An electric field withenergy at least two orders of magnitude smaller than a defibrillationshock is enough to unpin the rotating wave. Importantly, the preciselocation of the pinning center is not required. The effect is based onthe distribution of membrane potential generated near an obstacle in thepresence of an externally applied electric field.

This embodiment of the present invention provides a method for lowvoltage termination of an anatomical reentry in a patient heart. Inorder to accomplish the desired result, the electrical waveform for thepatient is detected and stored. The maximum negative derivative of theelectrical waveform for the patient is also recorded. Next, a set ofthreshold values for the waveform parameter is determined. The negativederivative of the electrical waveform is continuously calculated andcompared to the set of threshold values. A termination shock isdelivered by a suitable cardiac stimulation device, such as, forexample, as device containing a high voltage capacitor. The shock isdelivered to the patient's heart during a period reentry when thepatient-specific individually adjusted delay is provided after thenegative derivative exceeds the third threshold value.

If the shock was not delivered within the safety time period, aprescribed defibrillation shock can be delivered at the time ofexpiration of the safety time period. Alternatively, the prescribeddefibrillation shock can be delivered at the expiration of the safetytime period if it is determined that the reentry was not terminated bythe initial shock to the patient heart, as described above.

Referring now to FIGS. 11-17, details of the study of one embodiment ofthe present invention will be described. The study was performed toexperimentally validate the possibility and effectiveness of this newmethod in an in vitro acute model of the infarction border zone (BZ),which is known to provide the anatomical substrate for reentranttachycardia due to nonuniform conduction caused by remodeling of the BZ.Isolated superfused preparations of the rabbit right ventricular freewall were used in this study. The endocardial surface of the ventriclewas superfused as a model of the endocardial BZ. In this model, stablereentrant arrhythmias that were easily visualized using voltagesensitive dyes and fluorescent imaging techniques were obtained. Theseventricular tachycardias (VT) were driven by a single “mother rotor”reentrant source. Using low voltage shocks, we investigated mechanismsof unpinning and termination of “mother rotor” reentry pinned to amyocardial heterogeneity.

The study conformed to the guidelines of the American Heart Association.Experiments were performed in vitro on hearts obtained from New ZealandWhite rabbits (n=14) of both sexes weighing between 2-3 kg. The generalsteps of the experimental procedure have been described previously indetail in Nikolski V, Efimov I. “Fluorescent imaging of a dual-pathwayatrioventricular-nodal conduction system,” Circ Res. 2001; 88:E23-E30.Briefly, the rabbit was anesthetized intravenously with 50 mg/kg sodiumpentobarbital and 1000-2000 units heparin. Following a midsternalincision, the heart was removed and placed onto a Langendorff apparatus,where it was coronary perfused at 20 ml/min flow rate with warm (36°C.), oxygenated (95% O₂, 5% CO₂) modified Tyrode's solution of thefollowing composition (in mmol/L): NaCl 128.2, CaCl₂ 1.3, KCl 4.7, MgCl₂1.05, NaH₂PO₄ 1.19, NaHCO₃ 20 and glucose 11.1. Theexcitation-contraction uncoupler 2,3-butanedione monoxime (BDM, 15 mM,Diacetyl Monoxime, Sigma, St. Louis Mo.) was added to the perfusate toeliminate motion artifacts in optical recording caused by musclecontraction. The heart was stained with voltage-sensitive dyedi-4-ANEPPS (5 min, 1.3 μM). Following staining, the heart wasimmediately removed from the Langendorff apparatus and placed in a bathof ice cold Tyrode's solution. The right ventricular free wall wasdissected, stretched and pinned epicardial side down onto silicon disk.The preparation was then placed in a temperature controlled bath (36°C.) with Tyrode's solution where it was superfused at a rate of 80ml/min.

The optical mapping system used for voltage-sensitive fluorescentimaging as previously described in the general steps of the experimentalprocedure. Briefly, light produced by a 250 W quartz tungsten halogenlamp (Oriel) passed through a 520±45 nm excitation filter andilluminated the preparation. The fluorescence emitted from thepreparation was long-pass filtered (>610 nm) and collected by a 16×16photodiode array (C4675, Hamamatsu, Japan). The signal from thephotodiode array was amplified and digitized at a rate of 1500frames/sec.

A bipolar electrical recording from the preparation surface was used totrigger the shock application at the required phase of reentry. Thesignal was amplified with an isolation amplifier. A threshold detectordetermined the time of local activation and a shock was delivered acrosselectrode meshes located in the bath after a programmable delay. FIG. 11shows a block diagram of this setup. After amplification of the ECGsignal, a threshold detector was used to mark the time of excitation.From this time of local activation, a shock was delivered with aspecified delay. Field strength was calibrated with unipolar electroderecordings taken in the center of the chamber between the meshes. AKepco 100V regulated power supply (BOP-100-4M) was used a poweramplifier for delivering shocks, which were synthesized by adigital-to-analog controller integrated into a data acquisition system.

After a 15 min equilibration period, the field excitation threshold wasdetermined. Stable reentry was then initiated by a burst pacing at aninterval of 100-130 ms. Shocks consisting of 10 ms monophasic squarepulses were applied at an initial field strength of 0.25 V/cm. Thetiming of shock application was varied throughout the entire period ofreentry at 10 ms steps until the whole period of reentry was scanned. Ifthe full period of reentry was scanned and the reentry did notterminate, the magnitude of the shocks was increased in 0.1 V/cmincrements and scanning of the period was repeated. Once terminated,reentry was immediately reinitiated. If shocks were not applied, thestable reentry would last anywhere from 20 minutes to 1 hour (this wasthe longest time period we allowed the reentry to continue).

After 3 experiments, the preparation was embedded in Tissue-Tek® O.C.T.compound and frozen. The 16 μm transmural cryosections were mounted onpoly-L-lysine coated glass slides. Immunohistochemistry was conducted asdescribed previously. Briefly, double staining was performed with acommercially available anti-phosphorylated (Ser368) connexin 43 (Cx43)polyclonal antibody raised in rabbit (catalog no. AB3841, Chemicon) usedat a dilution of 1:400 and with a commercially availableanti-unphosphorylated (Ser368) Cx43 monoclonal antibody raised in mouse(catalog no. 13-8300, Zymed) used at a dilution of 1:200. Alexa fluor488 goat anti-mouse IgG₁ (catalog no. A-21121, Molecular Probes) andAlexa fluor 555 goat anti-rabbit IgG (catalog no. A-21428, MolecularProbes) were used as secondary antibodies at dilutions of 1:1000.Confocal imaging was then performed using a Nikon C1/80i confocalmicroscope.

Microscopy images were analyzed by determining the means of thenormalized phosphorylated Cx43 and unphosphorylated Cx43 signalintensities averaged over 1.26×0.080 mm² areas along and across thetissue surface. The depth of the surviving layer of tissue for eachsection was determined to be the distance at which the meanphosphorylated and unphosphorylated signal intensities intersected. Thedifferences between the phosphorylated and unphosphorylated signalintensities were analyzed by one-way repeated measurements ANOVA.

Phase plane analysis was performed on reentry data to determine thelocation of the reentry core which is indicated by a point of phasesingularity (PS). Specifically, the Bray-Wikswo method ofpseudo-empirical mode decomposition (PEMD) along with the Hilberttransform was used to generate the phase plane data. To determine linesof block created by the reentry cores, the PS trajectories were alsoobtained by tracking the locations of PS throughout one or more periodsof reentry. Activation maps were then created using two differentmethods. For paced data or reentry which included a three dimensionalpath (see FIGS. 16 a-16 d), activation maps were created by determiningthe local activation time (maximum of the first derivative)corresponding to each photo-diode signal. For the reentry data, afterphase-plane analysis was performed, isochronal maps were created bytracking the location of the wavefront in the phase plane throughout theentire period of reentry.

Rayleigh's test was used to determine if the phase of successful shockapplication was statistically different from a circular uniformdistribution. The concentration and angular mean of successful shockswere also determined. Data are presented as mean±standard error of mean.P-values less than 0.05 were considered significant.

The preparations were superfused. Thus, it was expected thatmidmyocardium would be subjected to ischemia and cellular uncoupling dueto dephosphorylation of Cx43.⁴⁵ Staining with anti-phosphorylated andanti-unphosphorylated Cx43 antibodies revealed that only a thin layer oftissue had phosphorylated Cx43 after 1-2 hours of superfusion, while themidmyocardium had only unphosphorylated Cx43. FIGS. 12 a-12 d show asummary of these results. A typical confocal microscopy image at 10×magnification is shown in FIG. 12 a. The endocardial superfused surfaceof this preparation is the left edge of the tissue section.Phosphorylated Cx43 is shown in red, with the signal extending from theendocardial surface to approximately 0.30 mm into the tissue.Unphosphorylated Cx43 is shown in green which becomes visible atapproximately 0.30 mm from the surface and extends to the edge of thephotograph. The averaged normalized signal intensities (see Methods) forthe preparation pictured in FIG. 12 a are shown in FIG. 12 b, again withphosphorylated Cx43 shown in red and unphosphorylated Cx43 shown ingreen. The depth of the surviving layer of tissue was determined to bethe intersection of these two signals, and for this preparation was0.299 mm. FIG. 12 c shows a surface plot of the signals across the widthof the tissue section pictured in FIG. 12 a before the means werecalculated. Combined results from 3 animals are shown in FIG. 12 d. Thephosphorylated and unphosphorylated signals were significantly differentthroughout the depth of the tissue (p=0.0036, one way repeatedmeasurements ANOVA). The average depth of tissue at which phosphorylatedCx43 was of higher density as compared to unphosphorylated Cx43 was0.38±0.10 mm.

In all studied preparations, the activation sequence during pacing andduring reentrant tachycardia induced by burst stimulation wascharacterized. Interestingly, in all preparations it was observed thatthe arrhythmias were driven by a single reentrant circuit in accordancewith the “mother-rotor” mechanism.

FIGS. 13 a-13 e illustrate typical results obtained from a singlepreparation for constant pacing and stable reentry. FIG. 13 a shows amap of activation produced by constant pacing applied with a cyclelength of 300 ms at the site indicated with a star. The black arrow ispointing to an area of crowded isochrones, indicative of slowconduction. A preparation photograph is shown in FIG. 13 b along withthe trajectories of PS obtained for two different stable reentriesobserved in this experiment, indicating the location of the core foreach reentry. Numbers in FIG. 13 b correspond to the location of eachoptical signal. The activation times (black circles) were determined bythe maximum of the first derivative. White circle at trace 1 indicatesactivation for the next rotation of reentry. The isochronal maps forthese reentries are shown in FIGS. 13 c-13 d, with the yellow corecorresponding to the isochronal map in FIG. 13 c and the cyan corecorresponding to the isochronal map in FIG. 13 d. The trajectories of PSare also shown on the isochronal maps in FIGS. 13 c-13 d. It is notsurprising that the reentry core in FIG. 13 c corresponds to the area ofslow conduction observed during constant pacing illustrated in FIG. 13a, as this area of slow conduction is heterogeneous with respect to thesurrounding tissue and provides the substrate to pin a reentrantarrhythmia. Several optical signals are shown in FIG. 13 e illustratingthe progression of activation around the reentry core illustrated inFIG. 13 d. The locations of the recording sites for each of the opticalsignals are shown with corresponding numbers on FIG. 13 b. Theactivation times determined for each signal as (−dF/dt)_(max) (whereF=fluorescence signal recording) are shown with black dots. The whitecircle in trace 1 indicates activation for the next rotation of reentry.

The first example of low-voltage termination of reentry presented hereis similar to the mechanism predicted by bidomain simulations of thepresent invention in which a “secondary source” of excitation is creatednear the reentry core immediately after shock application, presumablydue to the VEP mechanism at the heterogeneity serving as the reentrycore. FIGS. 14 a-14 f illustrate this example. The isochronal map forstable reentry is shown in FIG. 14 a, rotating counterclockwise with aperiod of 146.4 ms. FIG. 14 b shows the phase plane and location of PS(white dot) 1 ms prior to shock application. A shock of 0.63 V/cm wasthen applied. Ten ms after shock application, a new shock-inducedwavefront can be observed in the phase plane as indicated by thedepolarized red region near the PS in FIG. 14 c. Optical traces from thelocations indicated with corresponding colored boxes in FIG. 14 b areshown in FIG. 14 d and the surface ECG recording is shown in FIG. 14 e.The red optical trace appears unaffected by the shock, whereasshock-induced depolarization can be observed in the cyan optical trace.This new wave of depolarization then collided with the reentrantwavefront, unpinning it from the reentry core. The unpinned reentry thenmade two additional rotations with the core located far from the area ofpinning before it reached the edge of the preparation and terminated.Each termination of this reentry proceeded in a similar manner, with theunpinned reentry making anywhere from 0-3 additional rotations beforetermination at the border of the preparation. A polar plot of successfuland unsuccessful 0.63 V/cm shocks applied throughout all phases ofreentry is shown in FIG. 14 f. Successful shocks were clustered aroundthe angular mean with a concentration of 0.80. Rayleigh's test found thedistribution of successful shocks to be statistically different from auniform circular distribution (p<0.05).

Interestingly, reentry in all preparations was highly reproducible.Although, the exact location of the mother rotor could be different fromtachycardia induction to induction, it was always stationary.

The example of unpinning of reentry by virtual electrode-inducedexcitation of the reentry core without termination is similar to theprevious example in that a shock-induced secondary source of excitationnear the reentry core collided with and unpinned the reentry. However,in this case, the reentry did not proceed to the edge of the preparationand terminate. Instead, it pinned to a new location for several beats.After making 1-5 rotations around this new core, the reentry thenrepinned back to the original core, which apparently had strongerpinning force. The steady-state isochronal map for this reentry is shownrotating clockwise with a period of 131.0 ms in FIG. 15 a. Thephase-plane map 1 ms prior to shock application is shown in FIG. 15 b.The PS of the mother rotor is indicated with a white dot in the centerof the preparation. Additional PSs were present elsewhere in thepreparation due to transient block of conduction, however full rotationswere not maintained around these PSs. Ten ms after shock application, anew wavefront was created near the reentry core as indicated by thedepolarized red region in FIG. 15 c. Before shock application, adual-hump morphology is observed which indicates the presence of areentry core. After shock application, 3 full magnitude APs are recordedwhile the reentry is pinned to a new location. The reentry thenspontaneously repinned to the original reentry core and the dual-humpmorphology is again observed. This wavefront then collided with andunpinned the reentry. Although the reentry was unpinned, it immediatelyreattached to a new core, where it made several rotations beforespontaneously moving back to the original reentry core. Unpinning ofreentry was verified with optical signals recorded from locations nearthe original reentry core. One such signal is shown in FIG. 15 d. Thissignal was taken from a location near the original reentry coreindicated with a cyan box in FIG. 15 b. Before shock application, adual-hump morphology can be observed, indicating that this location isat the core of a reentrant arrhythmia. Immediately after shockapplication, the dual-hump morphology is no longer present and 3 fullmagnitude APs are recorded. The reentry then spontaneously repinned backto its original core and the dual-hump morphology can again be observed.The corresponding surface ECG recording is shown in FIG. 15 e. FIG. 15 fshows a polar plot of successful and unsuccessful shocks appliedthroughout all phases of reentry. Successful shocks were clusteredaround the angular mean with a concentration of 0.80. Rayleigh's testfound the distribution of successful shocks to be statisticallydifferent from a uniform circular distribution (p<0.001). Such unpinningwithout termination was observed in 1 preparation out of 14.

In 2 experimental preparations, reentry circuits were observed whichincluded a narrow isthmus of tissue. In these cases, low-voltagetermination was different than the previous examples. For thesereentrant circuits, the timing of shock application was not as criticalas it was for previous examples. Rather, termination was achieved atpractically any phase of reentry. This mechanism occurred when thereentry was rotating near the edge of the preparation or when thereentrant path included a 3D trabecular structure as in the examplepresented here. The activation map for this reentry is shown in FIG. 16a, with the reentrant pathway indicated with yellow arrows. In themiddle of the preparation, the pathway included a narrow trabecularstructure. As can be observed in the polar plot of successful andunsuccessful shocks in FIG. 16 b, termination of this arrhythmia had athreshold-like behavior. Successful shocks were found to have a very lowconcentration (0.46) around the angular mean which was not significantlydifferent from a circular uniform distribution. Below 0.51 V/cm,termination could not be achieved at any phase of reentry. However,above this value, termination could be achieved over many phases ofreentry. This observation was confirmed with Rayleigh's test which foundthe successful shocks to have a relatively low concentration (0.46)around the angular mean, which was not found to be statisticallydifferent from a uniform circular distribution (p>0.05). It is believedthat this phenomena occurred because 0.51 V/cm exceeded the fieldexcitation threshold for the trabecular structure present in thereentrant path. Once this structure became excited, it was eitherdepolarized or refractory when the reentrant wavefront approached thestructure. Because this narrow path was necessary to maintain thereentry, the wavefront had no alternative route and terminated. Anoptical trace from the location indicated with a cyan box in FIG. 16 ais shown in FIG. 16 c and the corresponding surface ECG recording isshown in FIG. 16 d.

In this study a total of 192 reentries were initiated and terminated orunpinned in 14 experimental animals. Across all animals, the averageperiod of reentry was 155.78±38.58 ms. Survival analysis found that E₈₀(shock strength at which 80% of reentries were terminated) was 1.21 V/cmwhich corresponds to 6.6 times the average field excitation threshold. Asurvival plot of the combined experiments is shown in FIG. 17, with thered dashed lines indicating the upper and lower 95% confidenceintervals. All reentries in all experimental animals were terminated atshock strengths at or below 2.74 V/cm.

In the present study, a new method of low voltage destabilization andtermination of ventricular reentrant tachyarrhythmias was investigatedin an appropriate model of the infarction BZ. Two different mechanismsof unpinning and termination of reentrant arrhythmias were observed inthis model; one of which was predicted by the theoretical investigationsand one of which was not.

The infarction BZ model used in this study was critical for manyreasons. First and foremost, immunohistochemistry results indicatedsurvival of only 0.38±0.10 μm of the endocardial superfused surface.This thin layer of surviving tissue provided an essentiallytwo-dimensional sheet of endocardium. This assured that the reentrantarrhythmia could be constantly visualized using optical imagingtechniques as there was no transmural progression of the reentry intothe mid-myocardial layers where optical imaging can no longer recordchanges in transmembrane potential. Also of great importance was theability of this preparation to sustain stable reentrant arrhythmias.This was likely due to slight variations in the depth of the infarctionBZ and levels of phosphorylated Cx43. Peters and colleagues observedthat pathways of reentrant circuits and functional lines of blockoccurred in regions where the surviving layer of the infarction BZ wasthinnest in a canine model of the epicardial BZ. (Peters N S, CoromilasJ, Severs N J, Wit A L., “Disturbed connexin43 gap junction distributioncorrelates with the location of reentrant circuits in the epicardialborder zone of healing canine infarcts that cause ventriculartachycardia,” Circulation. 1997; 95:988-996)

In this study, two mechanisms of low-voltage destabilization ofreentrant arrhythmias were observed in the superfused endocardial modelof the infarction BZ. The first of these mechanisms was predicted withbidomain models of anatomically-defined reentry by the theoreticalinvestigations where appropriately-timed VEP-induced excitation of thereentry core interacts with the reentry causing unpinning and possiblesubsequent termination. This mechanism was observed in all experimentalpreparations in the present study and is illustrated in FIGS. 14 a-14 eand FIGS. 15 a-15 f. After unpinning of the reentrant arrhythmia, thepredominant result in this isolated ventricular free wall wastermination of the reentry when it reached the edge of the preparation.However, this was not the only observed result and immediate terminationwould not necessarily be expected in a whole heart model. FIGS. 15 a-15f illustrate an example where once unpinned, the reentry immediatelyrepinned to another heterogeneity on the preparation. This behaviorwould be expected in a whole heart where much heterogeneity exists thatcould act to repin the reentry.

To avoid immediate repinning and facilitate complete termination of theunpinned reentry, one embodiment of the present invention usesanti-repinning (ARP) pulses applied after the low voltage unpinningshocks. Conventional ATP has difficulties terminating anatomical reentrywhen the pacing site is located at a distance from the reentry core.However, there are no such difficulties associated with ATP terminationof a functional reentry. Therefore, once the reentry is unpinned fromits anatomical core, ARP pulses can be effectively administered forterminating these now functional reentries and preventing theirreattachment to a new core.

The second observed mechanism of low voltage termination occurred whenthe reentrant path included a small isthmus of tissue. These paths werepresent when the reentry was rotating near the edge of the isolatedpreparation, or when the reentrant path included a three-dimensionaltrabecular structure. In these instances, termination was alwaysimmediate; reentry was never effectively “unpinned,” freely rotatingabout the tissue. The timing of shock application in these instances wasnot critical and exhibited a threshold-like behavior. Below a certainthreshold, termination could not be achieved. However, above thisthreshold, termination could be achieved at all phases of the reentryperiod. An example of one such reentrant path along with successful andunsuccessful shock applications is illustrated in FIGS. 16 a-16 d. Thismechanism of termination was observed for 4 different reentries in 2different experimental animals. It is believed that both thethreshold-like behavior and time-independence of this mechanism is dueto the isthmus of tissue itself. The threshold of termination likelycorresponds to the field excitation threshold of the isthmus. Shocksapplied below this threshold will have little or no effect on thereentry. However, shocks applied above this threshold will excite theisthmus. Because the narrow isthmus is essential for maintenance of thereentry, when the reentrant wavefront reaches this now excited orrefractory tissue, no other pathway exists for the reentry and itimmediately terminates.

Regardless of the mechanism of unpinning and/or termination, thedestabilization of a reentrant arrhythmia using this method can beachieved at significantly lower voltage gradients (VGs) than thoserequired for conventional defibrillation. A recent study by Niemann andcolleagues measured intracardiac VGs during transthoracicdefibrillation, and found that for commercially available devices,intracardiac VGs can reach up to 33 V/cm for monophasic waveforms and upto 24 V/cm for biphasic waveforms. (Niemann J T, Walker R G, RosboroughJ P, “Intracardiac Voltage Gradients during TransthoracicDefibrillation: Implications for Postshock Myocardial Injury,” AcadEmerg Med. 2005; 12:99-105). Similar studies have yet to be performedfor defibrillation shocks administered with ICDs, although it isgenerally well known that the goal for an ICD is to create VGs of atleast 5-10V/cm and it is likely that the VGs would be of similarmagnitude to transthorasic defibrillation and perhaps much larger nearthe shock electrodes where VGs are more than 20 times greater than theweakest VG more distant from the electrode. Although the concept of a“threshold level” for myocardial dysfunction is ambiguous, studies ofthe effects of strong shocks on papillary muscles and ventricular musclefibers have found the thresholds for electroporation and subsequentarrhythmogenic responses in these tissues to be as low as 15 V/cm and 34V/cm, respectively. (Kodama I, Shibata N, Sakuma I, Mitsui K, Iida M,Suzuki R, Fukui Y, Hosoda S, Toyama J. Aftereffects of high-intensity DCstimulation on the electromechanical performance of ventricular muscle.Am J Physiol. 1994; 267:H248-H258; and Li H G, Jones D L, Yee R, Klein GJ. Defibrillation shocks produce different effects on Purkinje fibersand ventricular muscle: implications for successful defibrillation,refibrillation and postshock arrhythmia. J Am Coll Cardiol. 1993;22:607-614).

The method of the present invention for low-voltage termination ofreentrant arrhythmias may be free from these adverse side effects ofhigh VG shocks. The accepted VG for conventional defibrillation shocks(to defibrillate 80% of the time) is 5.4±0.8 V/cm for a 10 ms monophasicwaveform. (Zhou X, Daubert J P, Wolf P D, Smith W M, Ideker R E,“Epicardial mapping of ventricular defibrillation with monophasic andbiphasic shocks in dogs,” Circ Res. 1993; 72:145-160). If this is theminimum VG required everywhere in the myocardium, and if this shock isdelivered from an electrode on the heart, one can again consider thatVGs nearest the electrode will reach magnitudes of more than 20 timesthe weakest VG. This results in VGs of over 100 V/cm near the electrode,which greatly exceeds the threshold for electroporation andarrhythmogenesis in some cardiac tissue. In the present study, it wasdetermined that 80% of initiated reentries could be terminated with a VGof 1.21 V/cm (10 ms monophasic waveform) when shocks were effectivelyapplied at the correct phase within the period of reentry. Thiscorresponds to a 20-fold reduction (5.4/1.21)² in defibrillation energy.This is likely to result in much less severe damage and resultingmyocardial dysfunction.

The method of termination, low voltage unpinning shock in accordancewith the present invention combined with ARP pulses may be a powerfulnew clinical tool for treating fast VT and fibrillation. The significantreduction of energy provided by this method may allow for painlessdefibrillation.

Recording of VEP induced by low voltage shocks is a challenge due to therelatively low signal-to-noise ratios of optical signals in thissuperfused preparation and to the low amplitude of the shock-inducedVEP. Thus, the study was unable to directly measure VEP at tissueheterogeneities.

Unpinning shocks alone is not likely to effectively terminate VT or VFin the human heart due to the larger size of the heart. The preparationsin the study were relatively small so that in 13 out of 14 preparations,unpinning resulted in quick drift of reentry toward the edge of thepreparation and termination. This is an unlikely scenario in the largemammalian heart. The study did not address this limitation, which couldbe resolved by subsequent application of ATP as described elsewhere inthis specification.

The experiments described above were conducted in superfused in vitropreparations in which only a thin endocardial layer survives after 30-40minutes of ischemia of midmyocardial and epicardial layers as shown inFIGS. 18 a-18 c. This is a model of acute phase of infarction, in whicharrhythmias are induced with significantly higher likelihood andreproducibility as compared to coronary perfused preparations or intactheart. Arrhythmia induction and termination is best in this preparationwith some modifications because it offers the unique possibility to mapelectrical activity from entire available myocardium. However, itremains to be shown that arrhythmias could be reproducibly induced andmapped in hearts with chronic healed infarct. A preliminary study on amodel of healed infarction, Li L, Nikolski V P, Wallick D W, Efimov I R,Cheng Y, Mechanisms of enhanced shock-induced arrhythmogenesis in therabbit heart with healed myocardial infarction, Am. J. Physiol., 2005,revisions subm, the disclosure of which is hereby incorporated byreference herein, and which fully supported the hypothesis of thepresent invention.

Referring to FIGS. 18 a-18 c and FIGS. 19 a-19 d, in this modelinfarction was induced by ligature of left marginal artery duringsterile surgery. Animals were allowed to recover for 1-8 weeks prior toin vitro study. As evident from FIGS. 18 a-18 c, direct perfusion fromventricular cavities allows survival of a thin layer of myocardium inthe rabbit heart during acute phase and during healing of infarction.FIG. 18 a shows anti-Cx43 staining reveals that only a thin 100-200 μmendocardial layer of cells, which remain coupled with gap junctionalchannel after 1 hour of ischemia. Deeper layers of cells uncouple due todephosphorylation of Cx43. FIG. 18 b shows triple immunostaining revealsthat only a 2-cell thin layer of myocytes remains in this 4-weekinfarction border zone. As evident from Cx43 staining (red) these cellsare coupled with gap junctional channels and are surrounded with largenumber of fibroblasts (blue). FIG. 18 c shows histology Masson trichromestaining reveals that the entire endocardial layer of this massiveinfarct survives as a thin layer of endocardial border zone (EBZ). Thissection contains a free wall and a papillary muscle that were replacedwith a scar during healing of infarction, except for 50-200 μmendocardial layers. No myocytes survived at the epicardium, which wasentirely scarred.

Preliminary data shows that this layer of tissue is responsible for ahigh propensity of arrhythmogenesis in agreement with studies by Peterset al in canine model of infarction. (Sambelashvili A., Nikolski V.,Efimov I. R., Nonlinear effects in subthreshold virtual electrodepolarization, Am. J. Physiol. Heart Circ. Physiol. 2003,284(6):H2368-H2374). Data shows that expression of Cx43 is disrupted inthis border zone (BZ) layer. Heterogeneities of Cx43 ion channelexpression provide the ionic substrate for reentry. Another candidate issignificant proliferation of fibroblasts, which could be coupled via gapjunctions to the myocytes in the EBZ and thus alter source-sinkrelationship creating conditions for slow conduction and reentry. FIGS.19 a-19 b illustrate significantly enhanced arrhythmogeneisis in thismodel (left panel) and the prominent role of the BZ layer in it. FIG. 19a shows vulnerability to arrhythmias was evaluated by monophasic shocksof either polarity applied at varying phase of action potential. Heartswith infarct were significantly more inducible. In FIG. 19 b, theprobability of reentrant wavefronts to occur at different anatomicallocations is shown. Areas of infarction border zone were always involvedin sustaining reentry.

FIG. 20 illustrates preliminary results from a version of a model of therabbit heart with acute and chronic states of infarction. 3Dvisualization of electrical activity in the Langendorff-perfused rabbitheart. Left three panels show three projections of the heart as they areseen by three photodiode arrays. Next three panels show maps oftransmembrane potential recorded by corresponding PDAs. Next threepanels show raw optical data V_(m) recorded during sinus rhythm fromrecorded sites shown with circles in the left panels. Right lower panelshows 3D surface reconstruction of the heart and 3D distribution oftransmembrane potential at a given time.

An elegant demonstration of the role of anatomical heterogeneities inthe initiation and maintenance of reentry near the healed scar has beendescribed in the literature. Sambelashvili A., Nikolski V., Efimov I.R., Nonlinear effects in subthreshold virtual electrode polarization,Am. J. Physiol. Heart Circ. Physiol. 2003, 284(6):H2368-H2374; and F.Aguel, J. Eason, N. Trayanova. Advances in modeling cardiacdefibrillation, IJBC, 13:3791-3805, 2003 These and numerous precedingstudies set the stage for understanding the role of structural andmolecular remodeling at the infarction border zone (IBZ) in thestabilization of reentrant circuits at the IBZ. In one embodiment of thepresent invention, three models of different stages of infarction in therabbit heart were developed, which allow accurate documentation of thereentrant circuit and its termination during defibrillation. Thesemodels include: superfused and coronary perfused isolated RV free wallpreparation to model the acute phase of infarction, isolated preparationfrom hearts with healed myocardial infarction, and intactLangendorff-perfused rabbit heart with healed myocardial infarction.These three models allow the systematic study of the application of themethod of the present invention with appropriate spatial-temporalresolution. In particular, it is believed that in the model of coronarydisease utilized by the present invention, reentrant arrhythmias arestabilized and facilitated by scars and IBZ areas and that reentrantcircuits can pin to the scar and form a leading center of VT or VF.

A significant body of literature has presented convincing evidence ofvirtual electrode polarization during high energy defibrillation shocks.See, M. Hillebrener, J. Eason, N. Trayanova. Postshock arrhythmogenesisin a slice of the canine heart, J. Cardiovasc. Electrophys.,14:S249-S256, 2003; N. Trayanova, R. Gray, D. Bourn, J. Eason. Virtualelectrode induced positive and negative graded responses: New insightsinto fibrillation induction and defibrillation, JCE. 14:756-763, 2003;C. Larson, L. Dragnev, N. Trayanova. Analysis of electrically-inducedreentrant circuits in a sheet of myocardium, Annals Biomed. Eng.,31:1-13, 2003; Efimov I. R., Fibrillation or Neurillation: Back to thefuture in our concepts of sudden cardiac death? Circ. Res. 2003,92(10):1062-4. Editorial; Efimov I. R., Nikolski V. P., Diastolicshocking experience: do virtual anodes exist only during systole?, J.Cardiovasc. Electrophysiol., 2003, 14(11): 1223-4. Editorial; Efimov I.R., Biermann M., Zipes, D., Fast Fluorescent Mapping of ElectricalActivity in the Heart: Practical Guide to Experimental Design andApplications. In “Cardiac Mapping”, 2nd edition, eds. Shenasa M.,Borggrefe M., Breithardt G., Futura Publishing Co., 2003, p. 131-156;and Cheng Y., Li L., Nikolski V. N., Tchou P. J., Efimov I. R.,Shock-induced arrhythmogenesis is enhanced by 2,3-butanedione monoximeas compared with cytochalasin D, Am. J. Physiol., 2004, 286(1):H310-H318, all of which are incorporated herein by reference.

Imaging with voltage sensitive dyes has established that electric shocksproduce simultaneously areas of positive and negative polarization.These areas of positive and negative polarization are commonly referredto as areas of virtual cathodes and virtual anodes, respectively.Polarity and strength of polarization is determined by the strength ofthe virtual electrode or “activating function”, which depends on boththe field strength and on the tissue resistive properties. Microscopicand macroscopic resistive heterogeneities are particularly importantsources of virtual electrodes, because they strongly contribute to thegeneralized activating function via components of resistivity tensor, asdescribed in Takagi S., Pumir A., Pazo D., Efimov I., Nikolski V.,Krinsky V., Unpinning and removal of a rotating wave in cardiac muscle.Phys. Rev. Let., 2004, 93: 05810, the disclosure of which is herebyincorporated by reference herein.

The present invention further hypothesize that scars and other sourcesof resistive heterogeneity facilitate shock-induced polarization via theeffect known as “virtual electrode” polarization or interchangeably“secondary source” formation. Thus, one embodiment of the presentinvention takes advantage of the fact that the same anatomicalheterogeneities that facilitate sustained stable reentry also facilitateelectric-field induced transmembrane polarization in adjacent areas ofexcitable myocardium. Based on this observation, it is believed that alow energy shock will selectively affect areas that provide thesubstrate for the leading center(s) of VT/VF. Therefore, we will be ableto destabilize and terminate VT/VF with significantly lower energy ascompared with conventional defibrillation, in which termination ofactivity in nearly all cardiac cells is required.

The present invention overcomes the reasons that previous attempts atATP have not achieved effective unpinning of a reentry by recognizingthat unpinning reentry does not necessarily mean its subsequentautomatic termination. An unpinned anatomical reentry preferably must beterminated by another method. As previously described, in one embodimentof the present invention, anti-repinning (ARP) pulses generallyanalogous to anti-tachycardia pacing (ATP) pulses are employedimmediately after the low energy pulse to terminate any unpinnedreentry. Presently, low energy ATP is sometimes used as an alternativeto high energy defibrillation shock. Current ATP therapy is appliedprior to defibrillation shock at an empirically chosen frequency higherthan that of VT/VF. A defibrillation shock is then used as a last resortwhen ATP fails, which occurs in 10-30% of cases. In this embodiment ofthe present invention, these two events are reversed: a low-energyunpinning shock is applied first and ARP termination of the unpinnedreentry is applied second. Although ARP in accordance with the presentinvention is generally analogous to conventional ATP, the purpose andtiming of ARP pulses is not to control heart rate as is the case for ATPpulses. It is believed that the combination of appropriately-timed lowenergy shock with ARP in accordance with this embodiment of the presentinvention will allow significantly reduce defibrillation energyrequirements by increasing the efficacy of ARP pulses that are“preconditioned” with an unpinning shock. Preferably, the ARP pulses ofthe present invention will be delivered as near-field electricalstimulation pulses similar to pacing and ATP pulses. Alternatively, theARP pulses of the present invention may be delivered as far-fieldelectrical stimulation pulses.

Earlier studies of defibrillation have been impeded by the inability toobserve electrical activity from the entire surface of the heart.Several research laboratories have attempted to develop panoramicimaging, which would allow dynamic detection of wavefronts of excitationfrom the entire epicardium of a Langendorff-perfused heart. Previousapproaches employed CCD sensors, which typically produce lower signalquality as compared with photodiode array (PDA) sensors.

One embodiment of the present invention has utilized a PDA-basedpanoramic system with a high sampling rate (5000 frames/sec) andsignal-to-noise ratio (78±21). This new imaging system has 768individual optical channels (256×3) and 8 instrumental channels. Wedeveloped an integrated control software under LabVIEW (NationalInstruments) with an advanced custom-made toolbox for dynamic analysisand visualization of electrical activity on the entire epicardialsurface. FIG. 21 shows a schematic diagram and photograph of thepanoramic system. A 3D fast panoramic optical mapping system consists of3 16×16 photodiode arrays (Hamamatsu) and 3 arrays of super luminescentlight emitting diodes (LEDs). System allows continuous image acquisitionof electrical activity at 5000 frames/second from the entire surface ofthe heart, stained with voltage-sensitive dye di-4ANEPPS.

The mechanisms of formation of the post-shock wavefronts, phasesingularities, and scroll-wave filaments have been examined inSambelashvili A., Efimov I. R., Dynamics of virtual electrode-inducedscroll-wave reentry in a 3D bidomain model. Am. J. Physiol. 2004:287(4): H1570-81, the disclosure of which is hereby incorporated byreference herein. It has been demonstrated for the first time how VEPinduced phase singularity mechanism is responsible for I, U and O-shapedscroll wave formation in a simplified slab 3D active bidomain model. Inseveral experimental publications we have examined factors responsiblefor survival of wavefronts of break excitation, which are formed byvirtual electrode polarization. In particular, the role of sodium andcalcium channels was examined as described in Li L., Nikolski V., EfimovI. R., The effect of lidocaine on shock-induced vulnerability. J.Cardiovasc. Electrophysiol, 2003, 14: S237-S248; and Mowrey K A, EfimovI R, Cheng Y, Kinetics of Shock Induced Transmembrane polarization:Effects of Nifedipine and lidocaine, 2005, Am. J. Physiol., subm, thedisclosures of which are hereby incorporated by reference herein.

The role of shock waveform rate, and electrode configuration was alsoexamined in Qu F., Zarubin F., Nikolski V. N., Efimov I. R., The Gurvichdefibrillation waveform has lower defibrillation threshold than the Zollwaveform and the truncated exponential waveform in the rabbit heart,Can. J. Physiol. Phar. 2005, in press; Qu F., Li L., Nikolski V. P.,Sharma V., Efimov I. R., Mechanisms of Superiority of Ascending RampWaveforms: New Insights into Mechanisms of Shock-induced Vulnerabilityand Defibrillation, AJP, 2005, revisions subm; and Li L, Nikolski V P,Wallick D W, Efimov I R, Cheng Y, Mechanisms of enhanced shock-inducedarrhythmogenesis in the rabbit heart with healed myocardial infarction,Am. J. Physiol., 2005, revisions subm, the disclosures of which arehereby incorporated by reference herein.

In parallel, the mechanisms of scroll wave formation and termination inthe 3D bidomain model of the intact rabbit heart were investigated todetermine whether post-shock behavior is dependent on the number ofpre-shock functional reentrant circuits, and if so, what mechanisms wereresponsible. Shocks were applied to a 3D bidomain slice to terminateeither a single scroll wave (SSW) or multiple scroll waves (MSWs). TheED50 shock strength for SSW was found to be 13% less than that for MSWsindicating that a larger number of functional reentries resulted in anincreased DFT. Understanding the complex spatiotemporal dynamics ofpost-shock activity in the heart is exceedingly difficult. In the nextset of studies, non-linear dynamics tools were used to simplify thistask. Specifically, post-shock activity was studied in terms of thepost-shock phase singularities, which represent the organizing centersof reentrant activity. This provided a new opportunity to clarify theinteraction of the shock with the pre-shock phase singularities, toevaluate how the shock itself induced phase singularities, and toexamine the behavior of the post-shock singularities for failed andsuccessful shocks. The goal of mechanistically examining the interactionof VEP with the phase singularity of a scroll wave (SW) rotating in abidomain sheet of straight fibers was presented in T. Ashihara, T.Namba, M. Ito, T. Ikeda, K. Nakazawa, N. Trayanova. Spiral wave controlby a localized stimulus: A bidomain model study, J. Cardiovasc.Electrophys., 15:226-233, 2004, the disclosure of which is herebyincorporated by reference herein. It was found that this interactionresulted in one of three possible outcomes: SW shift, SW breakup, and noeffect.

In accordance with one embodiment of the present invention, it isrecognized that conventionally used truncated exponential waveformswhich are used in ICDs and some external defibrillators are not optimal.These waveform were developed based on hardware considerations dating 50years back. Based on our studies we suggested in these publications thatbiphasic sinusoidal Gurvich waveform, as described in Qu F., Li L.,Nikolski V. P., Sharma V., Efimov I. R., Mechanisms of Superiority ofAscending Ramp Waveforms: New Insights into Mechanisms of Shock-inducedVulnerability and Defibrillation, AJP, 2005, revisions subm, thedisclosure of which is hereby incorporated by reference herein.Alternatively, an ascending biphasic waveform as described in Li L,Nikolski V P, Wallick D W, Efimov I R, Cheng Y, Mechanisms of enhancedshock-induced arrhythmogenesis in the rabbit heart with healedmyocardial infarction, Am. J. Physiol., 2005, revisions subm, thedisclosure of which is hereby incorporated by reference herein, mayoffer a 20-30% improvement in defibrillation energy requirements.

The central idea of this superiority is based on observation that thecellular membrane has a time constant in 1-7 ms range depending on thestate of myocardium and pharmacological therapy. See, Mowrey K A, EfimovI R, Cheng Y, Kinetics of Shock Induced Transmembrane polarization:Effects of Nifedipine and lidocaine, 2005, Am. J. Physiol., subm. Thus,it cannot follow the rapid leading edge of the shock, which is usuallyin 1 microsecond range. As a result, application of a descending ramp orexponential waveform would result in incomplete utilization of deliveredenergy. Indeed, the membrane reaches its maximum polarization after adelay from the leading edge and then the charge dissipates by the end offirst phase of the shock, because of decaying activating function of adescending waveform. In contrast, ascending waveform keeps increasingactivating function through the duration of the waveform and membrane ispolarized at its maximum at the end of the 1^(st) phase. Thus, maximumutilization of the delivered energy is achieved during first phase. Thesecond phase will follow and terminate arrhythmogenic effects of thefirst phase.

The method described above is exemplary of the method of the presentinvention. The methods above may be accomplished by an external deviceor by an internal, implanted device. The methods above may beaccomplished using any number and configuration of electrodearrangements, such as endocardial, epicardial, intravenous, implantableor external, or any combination thereof, to deliver electrical cardiacstimulation in accordance with the present invention. Multiple pathelectrode configurations as contemplated for use with some embodimentsof the present as shown, for example, in U.S. Pat. Nos. 5,306,291 and5,766,226, the disclosure of each of which are hereby incorporated byreference herein.

It is contemplated that the method of the present invention can beutilized together with, or separate from, other pacing anddefibrillation therapies. For example, the present invention can beimplemented as part of an ICD where a high voltage defibrillation shockcan be delivered in the event that the method of the present inventionis unable to successfully convert a cardiac arrhythmia. Alternatively,the present invention could be implemented as part of a conventionalpacemaker to provide for an emergency response to a VT/VF condition inthe patient that would increase the chances of patient survival. Stillanother embodiment of the present invention could be implemented as partof an automated external defibrillator (AED) as part of the applicationof external electrical therapy for emergency response to a cardiacarrhythmia.

The methods of the present invention also contemplate the use of anynumber of arrangements and configurations of waveforms and waveshapesfor the electrical stimulation pulse(s). Known monophasic, biphasic,triphasic and cross-phase stimulation pulses may be utilized. In oneembodiment, the use of an ascending ramp waveform as described in thearticle entitled “Mechanisms of Superiority of Ascending Ramp Waveforms:New Insights into Mechanisms of Shock-induced Vulnerability andDefibrillation,” a copy of which is attached as Appendix A to U.S.Provisional Application No. 60/697,858, and the disclosure of which ishereby incorporated by reference herein.

The methods of the present invention also contemplate the use of anynumber of arrangement and configurations for the generation of theelectrical stimulation pulse(s). While conventional high voltagecapacitor discharge circuitry may be utilized to generate the lowerenergy stimulation pulse(s) in accordance with the present invention, itis also expected that alternative arrangements could be utilizedinvolving lower voltage capacitor arrangements, such as stacked,switched or secondary capacitors, rechargeable batteries, charge pumpand voltage booster circuits as described, for example, in U.S. Pat.Nos. 5,199,429, 5,334,219, 5,365,391, 5,372,605, 5,383,907, 5,391,186,5,405,363, 5,407,444, 5,413,591, 5,620,464 and 5,674,248, thedisclosures of each of which are incorporated by reference herein.Generation of the ARP pulses in accordance with the preferred embodimentcan be accomplished by any number of methods, including known methodsfor generating pacing pulses. Similarly, any number of known techniquesfor cardiac arrhythmia detection may be used in accordance with themethod of the present invention.

Various modifications to the method may be apparent to one of skill inthe art upon reading this disclosure. The above is not contemplated tolimit the scope of the present invention, which is limited only by theclaims below.

The invention claimed is:
 1. An implantable system for treatingventricular tachyarrhythmias, the implantable system comprising: aplurality of implantable electrodes; and an implantable therapygenerator operably connected to the plurality of implantable electrodes,the implantable therapy generator programmed to: detect a ventriculartachyarrhythmia in a heart of a patient; establish a termination windowassociated with the ventricular tachyarrhythmia; deliver an unpinningshock via the plurality of electrodes to the patient within thetermination window that generates a relatively low voltage field tocreate a depolarized region in the heart to extinguish the ventriculartachycardia by destructively interfering with a reentry wave associatedwith the ventricular tachyarrhythmia so as to effectively unpin thereentry wave, wherein the unpinning shock is delivered at an energy thatis higher than conventional anti-tachycardia pacing pulses and lowerthan an expected lower limit of vulnerability of the patient for theventricular tachyarrhythmia such that the relatively low voltage fieldcreated by the unpinning shock is sufficient to unpin the reentry wavefrom a location in the heart without increasing a risk of ventricularfibrillation.
 2. The system of claim 1 wherein the implantable therapygenerator is programmed to deliver multiple pulses for each unpinningshock, wherein at least two of the pulses are delivered throughdifferent electrode paths in order to present alternative wave fronts tothe reentry wave so as to produce an equivalent of a vector rotatingfield to the reentry wave.
 3. The system of claim 1 wherein theimplantable therapy generator is programmed to deliver at least oneanti-repinning pulse subsequent to delivering the at least one unpinningshock and within the termination window to extinguish the reentry wavethat is unpinned from the location in the heart, the at least oneanti-repinning pulse having an energy that is less than the at least oneunpinning shock.
 4. The system of claim 1 wherein the implantabletherapy generator is programmed to define the termination window as atime period based on a frequency of the ventricular tachyarrhythmia. 5.A method for treating ventricular tachyarrhythmias in a patient,comprising: providing an implantable therapy generator includingprogrammably-operably circuitry to be implanted in a patient andoperably connected to a plurality of implantable electrodes; andconfiguring the programmably-operably circuitry of the implantabletherapy generator to detect and terminate a ventricular tachyarrhythmia,including by: establishing a termination window associated with theventricular tachyarrhythmia; and deliver an unpinning shock via theplurality of electrodes to the patient within the termination windowthat generates a relatively low voltage field to create a depolarizedregion in the heart to extinguish the ventricular tachyarrhythmia bydestructively interfering with a reentry wave associated with theventricular tachyarrhythmias so as to effectively unpin the reentrywave, wherein the unpinning shock is delivered at an energy that ishigher than conventional anti-tachycardia pacing pulses and lower thanan expected lower limit of vulnerability of the patient for theventricular tachyarrhythmia such that the relatively low voltage fieldcreated by the unpinning shock is sufficient to unpin the reentry wavefrom a location in the heart without increasing a risk of ventricularfibrillation.
 6. The method of claim 5 wherein configuring theprogrammably-operably circuitry of the implantable therapy generator todeliver the unpinning shock includes delivering multiple pulses for eachunpinning shock, wherein at least two of the pulses are deliveredthrough different electrode paths in order to present alternative wavefronts to the reentry wave so as to produce an equivalent of a vectorrotating field to the reentry wave.
 7. The method of claim 5 whereinconfiguring the programmably-operably circuitry of the implantabletherapy generator causes deliver of at least one anti-repinning pulsesubsequent to delivering the at least one unpinning shock and within thetermination window to extinguish the reentry wave that is unpinned fromthe location, the at least one anti-repinning pulse having an energythat is less than the at least one unpinning shock.
 8. The method ofclaim 5 wherein configuring the programmably-operably circuitry of theimplantable therapy generator defines the termination window as a timeperiod based on a frequency of the ventricular tachyarrhythmia.
 9. Amethod for controlling an implantable therapy generator adapted to beimplanted in a patient and operably connected to a plurality ofimplantable electrodes, the method comprising configuring theimplantable therapy generator to: detect a ventricular tachyarrhythmiaina heart of a patient; establish a termination window associated with theventricular tachyarrhythmia; within the termination window, deliver anunpinning shock via the plurality of electrodes that generates arelatively low voltage field to depolarize a region in the heart forextinguishing the ventricular tachyarrhythmia by destructivelyinterfering with a reentry wave associated with the ventriculartachyarrhythmia so as to effectively unpin the reentry wave, wherein theunpinning shock is delivered at an energy that is higher thanconventional anti-tachycardia pacing pulses and lower than an expectedlower limit of vulnerability of the patient for the ventriculartachyarrhythmia such that the relatively low voltage field created bythe unpinning shock is sufficient to unpin the reentry wave from alocation in the heart without increasing a risk of ventricularfibrillation.
 10. The method of claim 9 wherein configuring theimplantable therapy generator to deliver the unpinning shock includesdelivery of multiple pulses for each unpinning shock, wherein at leasttwo of the pulses are delivered through different electrode paths inorder to present alternative wave fronts to the reentry wave so as toproduce an equivalent of a vector rotating field to the reentry wave.11. The method of claim 9 wherein configuring the implantable therapygenerator further includes delivery of at least one anti-repinning pulsesubsequent to delivering the at least one unpinning shock and within thetermination window to extinguish the reentry wave that is unpinned fromthe location, the at least one anti-repinning pulse having an energythat is less than the at least one unpinning shock.
 12. The method ofclaim 9 wherein configuring the implantable therapy generator definesthe termination window as a time period based on a frequency of theventricular tachyarrhythmia.